The primary goal of the current research proposal is to examine whether pharmacological interventions which alter glucocorticoids (GC ) levels will influence cocaine's behavioral and neurochemical effects in humans. There are three specific aims: #1) a within-subjects study of 15 cocaine addicts and their behavioral responses to a fixed-order, ascending dose regimen of intranasal cocaine after acute (<12hr) pretreatment with the synthetic GC prednisone, the cortisol synthesis inhibitor and GC receptor antagonist, ketoconazole, and placebo; # 2) a between-subjects randomized study of 45 cocaine dependent subjects (all HIV) and their behavioral responses to the same cocaine regimen before and after chronic (7 days) pretreamtent with either prednisone (n=15), ketoconazole (n=15), or placebo (n=15) and; # 3) parallel preclinical studies of the identical drug interventions in awake rhesus monkeys, including cocaine-induced psychomotor activity and concurrent in vivo microdialysis measures of basal and cocaine-induced brain dipamine and serotonin levels. We hypothesize that increasing GC (prednisone) levels will enhance cocaine- induced euphoria and neurochemical impact, and that inhibiting GC synthesis (ketocoazole) will diminish cocaine's effects. If confirmed in humans, our findings would provide strong evidence in support of a primary pathophyisiological role for GC in cocaine abuse and lead to novel pharmacotherapies for cocaine dependence. Peliminary data from in 7 cocaine addicts studied as part of # 1 are currently being analyzed.